C850Y
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialCysteine → Tyrosine at position 850 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.975, DynaMut2 ΔΔG -0.42 kcal/mol (destabilising). The C850 partner of C847Y in the inferred C847-C850 disulfide.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L817 | — | Lost |
| Hydrogen bond | C847 | C847 | Preserved |
| Polar contact | — | S816 | Gained |
| Polar contact | — | R818 | Gained |
| Polar contact | C847 | C847 | Preserved |
| Polar contact | A852 | — | Lost |
| Van der Waals | — | C847 | Gained |
| Hydrophobic | — | R818 | Gained |
| Hydrophobic | C847 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 850 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C850 within 5 Å of MET851 (2.5 Å), ASN849 (2.5 Å), and CYS847 (3.6 Å — partner of C847Y Atlas card, possible disulfide). The C847-C850 distance of 3.6 Å is the strongest disulfide-distance signal in this batch.
Replacing C850 with tyrosine eliminates this potential disulfide and introduces aromatic volume. Combined with C847Y (Atlas card adjacent), both ends of the inferred C847-C850 disulfide are now known to be pathogenic when mutated.
The |ΔΔG| of 0.42 reflects fold accommodation. AlphaMissense's 0.975 confirms severe functional consequence. pLDDT 74 is borderline but above the IDR threshold.
Druggability Assessment
Mechanism is loss of the inferred C847-C850 disulfide. Therapeutic strategy: same C847-C850 microregion as C847Y.
Why this matters
Feed this card to Wolfram Intelligence
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